Aldose reductase inhibitors for the treatment of diabetic polyneuropathy.

BACKGROUND: Polyneuropathy, a common complication of diabetes mellitus, causes pain and sensory and motor deficits in the limbs, and is also an important independent predictor of foot ulceration. Inhibiting the metabolism of glucose by the polyol pathway using aldose reductase inhibitors is a potential mechanism to slow or reverse the neuropathy's progression. OBJECTIVES: To assess the effects of aldose reductase inhibitors on the progression of symptoms, signs or functional disability in diabetic polyneuropathy. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (from January 1966 to May 2007), EMBASE (from January 1980 to May 2007) and LILACS (from 1982 to May 2007). We reviewed bibliographies of randomized trials identified, and contacted authors and experts in the field. SELECTION CRITERIA: We included randomized controlled trials comparing an aldose reductase inhibitor with control, and lasting at least six months. The primary outcome measure was change in neurological function, measured in various ways, including strength testing, sensory examination, and composite scores of neurological examination. Secondary outcome measures were nerve conduction studies, neuropathic symptoms, quality of life, occurrence of foot ulcers and adverse effects. DATA COLLECTION AND ANALYSIS: Trials included in the review were selected and assessed independently by at least two of us. Methodological criteria and study results were recorded on data extraction forms. MAIN RESULTS: Thirty-two randomized controlled trials meeting the inclusion criteria were identified. Many had significant methodological flaws. Change in neurological function, our primary outcome measure, was assessed in 29 trials, but sufficient data for meta-analysis were only available in 13 studies, involving 879 treated participants and 909 controls. There was no overall significant difference between the treated and control groups (SMD -0.25, 95% CI -0.56 to 0.05), although one subgroup analysis (four trials using tolrestat) favored treatment. A benefit for neuropathic symptoms was suggested by a group of trials using a dichotomized endpoint (improvement or not), but this was contradicted by another group of trials which measured symptoms on a continuous scale. There was no overall benefit on nerve conduction parameters (27 studies) or foot ulceration (one study). Quality of life was not assessed in any of the studies. While most adverse events were infrequent and minor, three compounds had dose limiting adverse events that lead to their withdrawal from human use: severe hypersensitivity reactions with sorbinil, elevation of creatinine with zenarestat, and alteration of liver function with tolrestat. AUTHORS' CONCLUSIONS: We found no statistically significant difference between aldose reductase inhibitors and placebo in the treatment of diabetic polyneuropathy. Any future clinical trials of aldose reductase inhibitors should be restricted to compounds proven to have substantial biological or preclinical advantages over previously tested agents.

ALS incidence in Nova Scotia over a 20-year-period: a prospective study.

OBJECTIVE: Previous studies have suggested that the incidence of amyotrophic lateral sclerosis (ALS) in Nova Scotia is relatively high and increasing over time. This study was performed to determine the current incidence of ALS in Nova Scotia and to compare this to data collected in 1984 and 1995. METHODS: All physiatrists and neurologists were surveyed on a monthly basis over one year to record all new cases of ALS diagnosed in Nova Scotia. Data was compared to that collected using similar methods in 1984 and 1995. To validate our methods, we also performed a retrospective study using a provincial health care database. RESULTS: There were 21 new ALS cases in Nova Scotia during the 2003 study period, yielding a crude incidence of 2.24/100,000. The age-adjusted incident rate for 2003 was 2.13 (95% CI = 0.11-4.15). The age-adjusted rate for 1995 was 2.3 (95% CI = 0.08-4.53) while the age-adjusted rate for 1984 was 2.22 (95% CI = 0.13-4.32). Analysis of provincial health records identified 24 cases of ALS and an age-adjusted incidence of 2.44/100,000. CONCLUSIONS: The age-adjusted incidence of ALS in Nova Scotia has remained stable over the period 1984-2003. The incidence is similar to that reported in several other parts of the world.

Progress in clinical neurosciences: Charcot-Marie-Tooth disease and related inherited peripheral neuropathies.

The classification of Charcot-Marie-Tooth disease and related hereditary motor and sensory neuropathies has evolved to incorporate clinical, electrophysiological and burgeoning molecular genetic information that characterize the many disorders. For several inherited neuropathies, the gene product abnormality is known and for others, candidate genes have been identified. Genetic testing can pinpoint a specific inherited neuropathy for many patients. However, clinical and electrophysiological assessments continue to be essential tools for diagnosis and management of this disease group. This article reviews clinical, electrophysiological, pathological and molecular aspects of hereditary motor and sensory neuropathies.

Minimum standards for electromyography in Canada: a statement of the Canadian Society of Clinical Neurophysiologists.

BACKGROUND: Electromyography (EMG) is a widely used diagnostic technique for disorders of the nervous system. The Canadian Society of Clinical Neurophysiologists (CSCN) promotes the education, evaluation and standards of EMG in Canada. A statement of practice standards was needed to clarify the position of the CSCN on several issues relevant to the practice of EMG. METHODS AND RESULTS: A subcommittee of the CSCN reviewed current patterns of practice and established guidelines for review by the CSCN. The guidelines developed by the subcommittee were reviewed by the CSCN and adopted as recommendations for EMG practice. The subcommittee was charged with formulation of a document for publication. CONCLUSIONS: This document deals with minimum standards for electromyographer education, laboratory operation, equipment and a variety of special circumstances relevant to the practice of EMG. The standards can be adopted by EMG laboratories to guide quality assurance.

EMG related anxiety and pain: a prospective study.

BACKGROUND: Electromyography (EMG) is a useful test, but unfortunately also painful. We frequently encounter patients who worry about its painful nature, but tolerate it very well. OBJECTIVES: We evaluated anxiety levels of patients referred for EMG to explore the possible correlating and contributing factors to high anxiety. METHODS: A structured questionnaire, including the State-Trait Anxiety Inventory was completed by patients immediately before EMG testing. Emergency, hospitalized, and seriously ill patients were excluded. RESULTS: Seventy-nine cases with ages ranging from 19-72 years (mean 43) were included. Thirty-five (44%) patients had a high pre-test anxiety level. The likelihood of high anxiety was increased if the patient was worried about the test (p < 0.001) or about other issues unrelated to the test or underlying diagnosis (p < 0.001), or was taking an anti-psychotic or anxiolytic drug (p = 0.008). The degree or source of knowledge regarding the test procedure, did not affect the pre-test anxiety level. CONCLUSIONS: The information about EMG testing received by patients in this group did not affect pre-test anxiety levels. The patient's expectations regarding the test did influence anxiety levels and this may reflect generalized anxiety regarding testing procedures or misinformation regarding the nature of the test, as patients in general reported a better than anticipated experience following the test.

Using problem-based learning in neurosciences education for medical students.

BACKGROUND: A Curriculum Task Force proposed problem-based learning as one important educational strategy and recommended changes to a traditional medical curriculum. METHODS: This paper describes how a problem-based learning course in neurosciences was developed and has evolved since its inception in the Dalhousie University Faculty of Medicine. The curriculum planning and design phases are outlined, followed by a description of how the course has been implemented and evaluated. RESULTS: Program evaluation results are presented, describing student performance on examinations and their feedback about the course. CONCLUSION: The authors summarize lessons learned and identify future issues to continue the ongoing development of the course.

Symptoms experienced by patients with carpal tunnel syndrome.

BACKGROUND: Patients with carpal tunnel syndrome (CTS) sometimes report sensory symptoms outside the median nerve distribution. This study was designed to provide a more detailed assessment of these symptoms. METHODS: Patients with clinical suspicion of upper limb neuromuscular lesions were divided into those with electrodiagnostic (EDX) evidence of CTS, and those without. CTS patients with superimposed nerve abnormalities were excluded. Motor and sensory symptoms were assessed in the exclusive CTS patients. RESULTS: Over 50% of patients with exclusive CTS reported tingling or numbness over the whole hand, ulnar or radial nerve distributions. Some patients reported symptoms proximal to the wrist. Sensory signs did not extend beyond the median nerve distribution. Numbness and nocturnal pain were predictive of positive EDX evidence of CTS. CONCLUSIONS: Sensory symptoms outside the distribution of the median nerve are common in CTS. For enhanced sensitivity in diagnosis it is useful to be aware of these "atypical" symptoms. Reports of numbness and nocturnal pain are strong indicators of CTS.

Nerve microvessel changes in diabetes are prevented by aldose reductase inhibition.

BACKGROUND: Despite the potential importance of endoneurial microvessel abnormalities in diabetic neuropathy, the pathogenesis of these abnormalities is incompletely understood. We wished to evaluate the effect of experimental diabetes on endoneurial microvessels and determine if an aldose reductase inhibitor alters any of the changes induced by diabetes. METHODS: We compared streptozocin diabetic rats with and without aldose reductase inhibitor treatment to non-diabetic rats after 10 months of diabetes. Transverse microvessels from the mid-sciatic level were studied by electron microscopic morphometric evaluation. RESULTS: Microvessel endothelial, pericyte, basement membrane and total mural area were greater in untreated diabetic animals than non-diabetic animals. Aldose reductase inhibitor treated diabetic animals had greater endothelial area and possibly pericyte area but not basement membrane or total mural area. CONCLUSIONS: This study demonstrates that endoneurial microvessel abnormalities can be detected in experimental diabetic neuropathy. Microvessel basement membrane thickening will be prevented by an aldose reductase inhibitor. One mechanism by which abnormal polyol pathway activity may contribute to diabetic neuropathy could be through damage to microvessels.

Acute endothelial swelling is induced in endoneurial microvessels by ischemia.

Structural alterations of endoneurial microvessels occur in diabetic neuropathy and are statistically associated with severity of nerve fiber loss and teased fiber abnormality. It is therefore hypothesized that the microvessel alterations may cause or contribute to pathologic alterations of nerve fibers in diabetic neuropathy, possibly through hypoxic injury. The mechanism of the microvessel change in diabetic neuropathy is unknown. The role of microvessels and details of microvessel structure in other possible ischemic neuropathies has not been studied completely. Already there is evidence that hypoxia induces endothelial swelling but this has not been characterized or quantitated in nerve. To determine the acute morphologic effect of ischemia on ultrastructural features of transverse profiles of endoneurial microvessels major pelvic arteries were ligated in rats. At 36 h mean lumen and mural areas were greater in ischemic than in control nerves. All components (endothelium, pericytes and basement membrane) were on average greater in ischemic than controls. The greatest increase was in endothelial cells. In these cells swollen mitochondria were abundant. This study demonstrates that acute ischemia induces swelling of the cells and organelles of endoneurial microvessels.

The electrophysiologic profile of Dejerine-Sottas disease (HMSN III).

Electrophysiologic studies in 11 patients with Dejerine-Sottas disease (hereditary motor and sensory neuropathy type III, HMSN III) showed median and ulnar motor nerve conduction velocities less than 6 m/sec in all but 1 patient. Marked temporal dispersion without conduction block was present in all patients. Uniform slowing in adjacent motor nerves was consistent with other studies of inherited neuropathies, although marked temporal dispersion may make HMSN III more difficult to distinguish from acquired neuropathies than other hereditary conditions. The electrophysiologic features of HMSN III patients were significantly different from a series of patients with other hereditary neuropathies chosen because of very slow nerve conduction velocity.

Peripheral neuropathy: approach to numbness.

Peripheral neuropathy can cause numbness and many other distressing symptoms. Diagnosing the cause of neuropathy can prove to be a frustrating exercise for both the physician and the patient. After a few common diagnostic considerations are excluded, a physician can become discouraged by the long list of uncommon disorders that could produce peripheral neuropathy. The author presents an approach to diagnosing peripheral neuropathy and examines the limitations inherent in evaluating this problem.

Horner's syndrome and demyelinating peripheral neuropathy caused by high-dose cytosine arabinoside.

High-dose cytosine arabinoside may benefit patients with refractory acute leukemia. Peripheral nervous system disturbances caused by cytosine arabinoside have rarely been reported. We describe a patient with acute leukemia who developed Horner's syndrome and a severe demyelinating peripheral neuropathy leading to death after receiving high-dose cytosine arabinoside. Peripheral nerve dysfunction is a potentially serious complication of high-dose cytosine arabinoside.

Inner perineurial cell vulnerability in ischemia.

The perineurium of peripheral nerve plays important roles in anatomical organization of fiber groups, in endoneurial fluid homeostasis and in maintenance of tensile strength but little is known about the functional and structural alterations of the perineurium with injury. Large arteries of supply to lower limb of Sprague-Dawley rats were ligated to study the structural reactions of perineurium at 36 h and at 7 days after induction of ischemic injury. Lipid droplets were found to be an early reactive change to ischemia in multiple cell types including perineurial, endothelial and Schwann cells. In peripheral nerve levels showing early myelinated fiber injury the inner perineurial sheath was widened and was undergoing degeneration. The inner layers of perineurial cells showed swelling, organelle disruption and membrane dissolution while outer layers remained intact. Inner perineurial cell degeneration is a prominent early feature of ischemic injury and may be an important mechanism of altered endoneurial homeostasis, fiber function and structure.

Chronic hypoxia induces selective maldevelopment of peripheral myelin in rat.

To determine the morphologic effect of chronic hypoxia on peripheral nerve development, four-week-old rats were placed in a 10% O2 environment for ten weeks and compared with controls. Light microscopic morphometric analysis of hind limb nerves of hypoxic as compared to control nerves showed at statistically significant levels, a) smaller total fascicular areas, b) smaller median diameters, c) fiber spectra with peaks at smaller diameters, d) fewer large myelinated fibers per nerve, e) larger fiber density, f) smaller myelin areas. On average myelin areas, relative to axon size, were smaller in oxygen-deprived than in control rats. Also myelin spiral length and the number of myelin lamellae relative to axon area were smaller. These findings suggest that hypoxia retards myelinated fiber diameter and especially myelin development.

Nonsystemic vasculitic neuropathy.

Among 65 patients with necrotizing vasculitis, 45 had systemic and 20 had nonsystemic vasculitic neuropathy. In nonsystemic vasculitic neuropathy, clinically only nerves are affected; there are no, or few, constitutional symptoms or serological abnormalities. The clinical and pathological features are those of an ischaemic neuropathy caused by a necrotizing vasculitis of small arterioles. These 20 patients had neuropathic symptoms for a median time of 11.5 yrs (range 1-35 yrs). The clinical pattern of neuropathy was that of multiple mononeuropathy in 13, asymmetric neuropathy in 4, distal polyneuropathy in 3, and sensory polyneuropathy in 1. As compared with their initial evaluation, 8 are now worse, 5 are better, 4 are approximately the same, and 3 are dead from unrelated causes. Prednisone was thought to prevent the development of new lesions in some cases. By contrast, of the 41 patients with systemic necrotizing vasculitis whose outcome is known, 12 are dead (median time, 1.5 yrs, range 3 months-8 yrs) and 29 are alive (median time, 6 yrs, range 6 months-22 yrs).

Treatment of paramyotonia congenita with acetazolamide.

Treatment of paramyotonia congenita with acetazolamide has been shown to reduce myotonic symptoms but severe weakness has developed in some patients leading to a recommendation not to use the drug in this disorder. We studied a patient with the characteristic clinical and electrophysiological profile of paramyotonia congenita. Myotonia was effectively treated with a very low dose of acetazolamide and no weakness developed. We conclude that acetazolamide can be a safe and effective medication in paramyotonia congenita.

Compression and entrapment syndromes.

Family physicians are often confronted by patients who present with pain, numbness and weakness. Such complaints, when confined to a single extremity, most particularly to a restricted portion of the extremity, may indicate focal dysfunction of peripheral nerve structures arising from compression and/or entrapment, to which such nerves are selectively vulnerable. The authors of this article consider the paramount clinical features that allow the clinician to arrive at a correct diagnosis, reviews major points in differential diagnosis, and suggest appropriate management strategies.

Stationary waves recorded at the shoulder after median nerve stimulation.

A new recording method with a reference electrode on the stimulated arm defined two discrete far-field potentials just before the propagated near-field nerve action potential was recorded at Erb's point. Both potentials were stationary waves with the same latency at all recording sites. The first potential had the same onset and peak latencies as the propagated wave at the axilla; it corresponded to the first component of the P9 far-field potential recorded with scalp to noncephalic reference montages. The latency of the second potential coincided with that of the propagated wave entering the neck and corresponded to the peak of the P9 potential. The occurrence of these potentials where there are significant changes in the morphology of the volume conductor suggests that the P9 far-field potential is due to a change in the conducting medium that surrounds the nerve.